DNA interaction, antimicrobial and molecular docking studies of biologically interesting Schiff base complexes incorporating 4-formyl-N,N-dimethylaniline and propylenediamine

Article abstract of DOI:10.1002/aoc.3577

Four new transition metal complexes incorporating a Schiff base ligand derived from propylenediamine and 4-formyl-N,N-dimethylaniline have been synthesized using transition metal salts. The characterization of the newly formed complexes was done from phys

Full text of DOI:10.1002/aoc.3577

Received: 6 February 2016
DOI 10.1002/aoc.3577
Revised: 27 April 2016
Accepted: 2 July 2016
F U L L PA P E R
DNA interaction, antimicrobial and molecular docking studies of
biologically interesting Schiff base complexes incorporating
4
‐formyl‐N,N‐dimethylaniline and propylenediamine
*
Seemon Packianathan | Ganesan Kumaravel | Natarajan Raman
Research Department of Chemistry, VHNSN
Four new transition metal complexes incorporating a Schiff base ligand derived
from propylenediamine and 4‐formyl‐N,N‐dimethylaniline have been synthesized
using transition metal salts. The characterization of the newly formed complexes
College, Virudhunagar 626 001, Tamilnadu, India
Correspondence
Natarajan Raman, Research Department of
Chemistry, VHNSN College, Virudhunagar – 626
1
was done from physicochemical parameters and using various techniques like H
0
01, India.
1
3
NMR, C NMR, IR, UV, electron paramagnetic resonance and mass spectros-
copies, powder X‐ray diffraction and magnetic susceptibility. All the complexes
were found to be monomeric in nature with square planar geometry. X‐ray powder
diffraction illustrates that the complexes have a crystalline nature. The interaction of
metal complexes with calf thymus DNA was investigated using UV–visible absorp-
tion, viscosity measurements, cyclic voltammetry, emission spectroscopy and
docking analysis. The results indicate that the Cu(II), Co(II), Ni(II) and Zn(II) com-
plexes interact with DNA by intercalative binding mode with optimum intrinsic
E‐mail: ramchem1964@gmail.com
4
4
4
4
−1
binding constants of 4.3 × 10 , 3.9 × 10 , 4.7 × 10 and 3.7 × 10 M , respectively.
These DNA binding results were rationalized using molecular docking in which the
docked structures indicate that the metal complexes fit well into the A‐T rich region
of target DNA through intercalation. The metal complexes exhibit an effective cleav-
age with pUC19 DNA by an oxidative cleavage mechanism. The synthesized ligand
and the complexes were tested for their in vitro antimicrobial activity. The com-
plexes show enhanced antifungal and antibacterial activities compared to the free
ligand.
KEYWORDS
antimicrobial study, DNA binding, molecular docking analysis, propylenediamine
[
6]
1
| INTRODUCTION
research. They are also very useful model systems in che-
late chemistry. The metal ion of the complexes can be coordi-
nated by the imine nitrogen atom and also other active centres
present in the molecule. These can be lead to many interest-
Schiff bases are an important class of inorganic and organic
compounds with a variety of uses. They have been widely
engaged as ligands in the formation of transition metal com-
[
7–9]
ing catalytic and other potential properties.
In recent
[
1,2]
plexes.
Schiff bases containing heterocyclic moieties pos-
decades, metallocomplexes have attracted much attention in
chemistry, biochemistry and pharmacology as hopeful com-
pounds for the creation of novel drugs. Propylenediamine
sess more interesting properties due to their diverse
anticancer, antiviral, fungicidal, bactericidal, anti‐inflamma-
[3,4]
tory and anti‐HIV activities.
Thus, the development of
derivatives
of
the
type
[PtCl (N‐benzyl‐1,3‐
2
new chemotherapeutic Schiff bases is now attracting the
propanediamine) ] have been reported as potential antitumor
2
[5]
attention of medicinal chemists. The chemistry of Schiff
base compounds as well as their metal complexes is of great
interest in various fields of chemical and biological
agents.
Antimicrobial and DNA‐binding studies are very impor-
tant in the development and advancement of new therapeutic
Appl. Organometal. Chem. 2016; 1–14
wileyonlinelibrary.com/journal/aoc
Copyright © 2016 John Wiley & Sons, Ltd.
1

2
S. PACKIANATHAN ET AL.
reagents and DNA molecular probes. 10–12] Recently, there has
been tremendous interest in studies associated with the interac-
tion of transition metal ions with nucleic acids and the impor-
tant development of new reagents for biotechnology and
[
the complexes were recorded with a Shimadzu model 1601
UV–visible spectrophotometer in the wavelength range
200–1100 nm. FT‐IR spectra were recorded with a Shimadzu
model IR‐Affinity‐1 spectrophotometer using KBr pellets in
[
13]
−1
medicine.
Metal complexes with their variable coordina-
the range 350–4000 cm . Proton NMR spectra of the ligand
tion environment and adaptable redox and spectral properties
have been proposed for designing species that are suitable to
and the complexes were recorded with a Bruker Avance DRX
300 FT‐NMR spectrometer using tetramethylsilane as the
internal standard. Room temperature magnetic susceptibility
measurements were carried out with a modified Gouy‐type
magnetic balance (Hertz SG8‐5HJ). The room temperature
molar conductivity of the complexes in DMSO solution
(10 M) was measured using a Deep Vision 601 digital
conductometer. The X‐band EPR spectra were obtained at liq-
uid nitrogen temperature (77 K) using tetracyanoethylene as
the g‐marker. Redox properties of complexes were deter-
mined with a CHI 620C electrochemical analyser. The mea-
surements were carried out under nitrogen atmosphere
using a three‐electrode cell in which a glassy carbon, satu-
rated Ag/AgCl and platinum wire were used as the working,
reference and auxiliary electrodes, respectively. Powder X‐
ray diffraction patterns were recorded with an X'Pert PRO
[14]
bind to and cleave DNA. Small molecules can interact with
DNA through the following three non‐covalent modes: inter-
calation, groove binding and external electrostatic effects.
Among these interactions, intercalation is one of the most
important DNA‐binding modes, which is related to the
antitumor activity of a compound. Small metal complexes
undergo hydrolytic DNA cleavage which is very useful in
genetic engineering molecular biotechnology and robust
−
3
[
15,16]
anticancer drug design.
Recently, there has been a great
[
17–23]
interest in the binding of metal complexes with DNA
because it may provide important information for new can-
cer therapeutic agents and potential probes of DNA struc-
ture and conformation. Hence, much attention has been
targeted on the design of metal‐based complexes, particu-
larly transition metal complexes which can bind to and
cleave DNA effectively.
It is our aim to design an appropriate ligand to obtain the
optimum metal complex to resolve the challenges that have
arisen earlier. Thus, encouraged by the advancements
discussed above, herein we report our newly synthesized
Schiff base transition metal complexes derived from a
bidentate Schiff base ligand (using 4‐formyl‐N,N‐
dimethylaniline and propane‐1,3‐diamine) together with their
characterization by employing the techniques of Fourier
transform infrared (FT‐IR), UV–visible and electron para-
magnetic resonance (EPR) spectroscopies, ESI‐MS and pow-
der X‐ray diffraction. Furthermore, interaction of the metal
diffractometer using Cu Kα radiation (λ = 1.54060 Å) with
1
an operating voltage of 40 kV and a current of 30 mA. All
fluorescence emission measurements were performed with a
JASCO spectrofluorimeter (FP6200) using a quartz cuvette
of 1 cm path length.
2
.2 | Preparation of Schiff base ligand (L)
Synthesis of the Schiff base was done by the dropwise addi-
tion of an ethanolic solution of 4‐formyl‐N,N‐dimethylaniline
(0.02 M) to an ethanolic solution of propylenediamine
(0.01 M). The reaction mixture was refluxed for 3 h. A pale
yellow coloured solution was obtained. Then the solution
was reduced to one‐third using a water bath. The precipitated
solid complex was filtered off, washed thoroughly with etha-
nol and dried in vacuo. The yield was 77%. The analytical
and physical data of the Schiff base ligand and its complexes
are given in the supporting information (Table S1).
(II) complexes with DNA was also studied to get additional
features of their binding modes. Also, the bioactivity of these
complexes was assayed for Gram‐positive, Gram‐negative
and fungal strains.
[
C H N ]. Yield 82%. Anal. Calcd (%): C, 74.96; H,
21 28 4
8
.39; N, 16.65. Found (%): C, 74.48; H, 8.18; N, 16.48).
2
2
| EXPERIMENTAL
−
1
FT‐IR (KBr, cm ): 1610 ν(HC═N), 1220–1260
ν(C─N─C), 2900–2950 ν(C─H), 1400–1600 ν(C═C). H
NMR (DMSO‐d , δ, ppm): 6.8–7.5 (m, aromatic), 3.7
(N─CH ), 2.0 (CH ), 3.1 (N─CH ), 8.7 (HC═N).
1
.1 | Materials and methods
6
13
All chemicals used were of analytical reagent grade. 4‐
Formyl‐N,N‐dimethylaniline, propylenediamine, calf thymus
C
2
2
3
NMR (DMSO‐d , δ, ppm): 41.3 (C ), 153.4, 111.9, 124.6,
6
1
(
CT) DNA, pUC19 DNA and ethidium bromide (EB) were
152.0 (C ‐C ), 160.8 (C ), 53.4 (C ), 32.2 (C ). UV–visible
(DMSO, cm (transition)): 27 548 (π–π*), 38 759 (n–π*).
2
5
−
6
7
8
1
obtained from Sigma Aldrich. All metal salts were obtained
from E‐Merck and used without further purification. Sol-
vents dimethylformamide and dimethylsulfoxide (DMSO)
and agar were procured from Hi‐media Chemicals. The
solvents were purified by following the standard
2
.3 | Preparation of Schiff base metal complexes
An ethanolic solution of 0.001 M metal(II) chloride was
mixed with Schiff base ligand (0.001 M) and the resultant
mixture was stirred for 2 h. The reaction mixture was
refluxed for 3 h and then the solvent was evaporated under
[
24]
procedures.
Elemental analysis (C, H and N) data were obtained using
a PerkinElmer 240 elemental analyser. Electronic spectra of

S. PACKIANATHAN ET AL.
3
reduced pressure. The precipitated complexes were isolated
and washed with distilled water. They were recrystallized
from ethanol and dried in vacuum at room temperature.
bound form, respectively. From equation (1), slope 1/(ε − ε )
b
f
and intercept 1/K (ε − ε ) were determined. Finally by
b
b
f
comparing the identified slope and intercept, Kb was
[
CuLCl ]. Yield: 74%. Anal. Calcd for C H N Cl Cu
calculated.
2
21 28
4
2
(
5
1
%): C, 53.56; H, 5.99; N, 11.90; Cu, 13.49. Found (%): C,
−
1
3.18; H, 5.74; N, 11.82; Cu, 13.17. FT‐IR (KBr, cm ):
2
.5 | UV–visible spectroscopy
−
1 2
−1
571 ν(HC═N), 438 ν(M─N). Λ (Ω mol cm ): 18.09.
m
−
1
Absorption titration experiments were carried out by varying
the DNA concentration and maintaining the complex concen-
tration constant. Absorbance values were recorded after each
successive addition of DNA solution and equilibration (ca
10 min). The absorption data were analysed for an evaluation
μeff (BM): 1.94. UV–visible (DMSO, cm (transition)):
1 186 (d–d).
NiLCl ]. Yield: 71%. Anal. Calcd for C H N Cl Ni
2
[
2
21 28
4
2
(
5
1
%): C, 54.12; H, 6.06; N, 12.02; Ni, 12.59. Found (%): C,
−1
4.01; H, 5.91; N, 11.88; Ni, 12.41. FT‐IR (KBr, cm ):
−
1 2
−1
of the intrinsic binding constant K using a reported
b
604 ν(HC═N), 427 ν(M─N). Λ (Ω mol cm ): 12.57.
m
[
25]
−
1
procedure.
μeff (BM): diamagnetic. UV–visible (DMSO, cm (transi-
tion)): 14 727 (d–d).
2
.6 | Cyclic voltammetry
[
CoLCl ]. Yield: 73%. Anal. Calcd for C H N Cl Co
2 21 28 4 2
(
5
1
%): C, 54.09; H, 6.05; N, 12.01; Co, 12.64. Found (%): C,
Electrochemical studies were carried out using a CHI electro-
chemical analyser, controlled by CHI620C software. Cyclic
voltammetry measurements were performed using a glassy
carbon working electrode and an Ag/AgCl reference elec-
trode and the supporting electrolyte was 50 mM NaCl,
5 mM Tris buffer (pH = 7.2). All solutions were deoxygen-
ated by purging with nitrogen for 30 min prior to measure-
ments. The degree of reversibility of one‐electron transfer
reaction can be obtained from the difference between forward
and backward peak potentials. The ratio of equilibrium con-
stants for the binding of oxidative and reductive ions to
DNA was calculated using the Nernst equation:
−
1
3.93; H, 5.92; N, 11.92; Co, 12.47. FT‐IR (KBr, cm ):
−
1 2
−1
598 ν(HC═N), 445 ν(M─N). Λ (Ω mol cm ): 13.83.
m
−
1
μeff (BM): 3.42. UV–visible (DMSO, cm (transition)):
3 793, 12 642 (d–d).
ZnLCl ]. Yield: 68%. Anal. Calcd for C H N Cl Zn
1
[
2
21 28
4
2
(
5
1
%): C, 53.35; H, 5.97; N, 11.85; Zn, 13.83. Found (%): C,
−1
3.18; H, 5.82; N, 11.72; Zn, 13.65. FT‐IR (KBr, cm ):
1
597 ν(HC═N), 449 ν(M─N). H NMR (DMSO‐d , δ,
6
ppm): 6.8–7.5 (phenyl multiplet), 3.6 (N─CH ), 2.0 (CH ),
2
2
1
3
3
4
5
.1 (N─CH ), 8.9 (HC═N). C NMR (DMSO‐d , δ, ppm):
3
6
1.3 (C ), 153.4, 111.9, 124.6, 152.0 (C ‐C ), 162.3 (C ),
1
2
5
6
−
1
−1
2
3.8 (C ), 32.2 (C ). Λ (Ω mol cm ): 14.96. μ
7
8
m
eff
ꢀ
ꢁ
(
BM): diamagnetic.
Kred
Kox
0
b
0
f
E −E ¼ 0:0591× log
(2)
2
.4 | DNA binding assay
0
0
To carry out the DNA binding experiment using absorption
spectral titrations, an array of solutions was prepared in which
the concentration of the complex was maintained constant
where Eb and Ef are the potentials of the bound and free
complex forms, respectively, Kred is the binding constant for
the binding of reductive ion species with CT DNA and Kox
is the binding constant for the binding of oxidative ion spe-
cies with CT DNA.
(0.1 mM) while the concentration of stock CT DNA was
increased from solution to solution. The absorption spectra
of these different metal complex–DNA solutions were
obtained in the range 200–1100 nm. By measuring the alter-
ations in the ligand‐to‐metal charge transfer absorption band
upon increasing DNA concentration, the intrinsic binding
2
.7 | Viscosity study
Viscosity measurements at room temperature were carried
out using a semi‐microdilution capillary viscometer. Each
experiment was performed three times and an average flow
time was calculated. Data were presented as (η/η ) versus
binding ratio, where η is the viscosity of DNA in the presence
constants K were calculated. For such calculations, equation
b
(1) was employed by monitoring the changes of absorption in
the metal‐to‐ligand charge transfer band with increasing con-
centration of DNA:
0
of complex and η is the viscosity of DNA alone.
0
½
DNAꢀ ½DNAꢀ
1
¼
þ
(1)
2
.8 | DNA cleavage
εa−εf
εb−εf
½Kbðεb−εfÞꢀ
For a solution of pUC19 DNA in buffer (50 mM NaCl/5 mM
Tris–HCl; pH = 7.2), the ratio between the UV absorbance at
260 and 280 nm (A260/A280) was 1.89. This suggested that
the chosen DNA was sufficiently free of proteins. To accom-
plish cleavage reactions, solutions of pUC19 DNA were pre-
pared and then diluted with loading dye using 1% agarose
In the above equation, [DNA] denotes the concentration
of DNA and absorption coefficients ε , ε and ε correspond
a
f
b
to Aobs/[complex], free complex extinction coefficient and
the extinction coefficient of the complex in the totally

4
S. PACKIANATHAN ET AL.
−1
gel. To each solution obtained, 3 μl of EB (0.5 μg ml ) was
added and mixed well. In the next step, warm agarose was
poured and instantly held tightly with a comb to develop sam-
ple wells. The gel was placed in an electrophoretic tank and
adequate electrophoretic buffers were added to enclose the
gel to 1 mm depth. DNA sample (20 μM), 30 μM complex
and 10 μM H O in the aforesaid buffer (pH = 7.2) were mixed
2
2
with a loading dye and filled into the well of the submerged gel
using a micropipette. A 50 mA electric current was passed and
the gel was taken out from the buffer. The gel was photograph-
ically captured under UV light after the completion of
electrophoresis.
2.9 | Antimicrobial activity
Antibacterial and antifungal activities of the ligand and the
synthesized metal complexes were tested in vitro against the
bacterial species K. pneumoniae, B. subtilis, E. coli and S.
typhi and the fungi A. flavus, C. albicans and A. niger using
the paper disc method with nutrient agar as the medium.
Ampicillin was used as the standard antibacterial agent and
ciprofloxacin was used as the standard antifungal agent.
The test organisms were grown on nutrient agar medium in
Petri plates. Discs were prepared and applied over the long
culture. The compounds were prepared in DMSO and soaked
in filter paper disc of 5 mm in diameter and 1 mm in thick-
ness. The concentrations of ligand and the complexes used
SCHEME 1 Schematic route for synthesis of metal complexes
3
.1 | FT‐IR spectra
FT‐IR spectra afford important information regarding the
coordinating sites of a ligand. The FT‐IR spectra of the com-
plexes were compared with that of the free ligand to deter-
mine the changes that might have taken place during the
complexation. The ligand exhibited a band at 1610 cm
which is assigned to the azomethine nitrogen. In the free
−1
ligand spectrum the absorption band measured at 1220–
−
1
in this study were 0.01 μg ml . The discs were placed on
previously seeded plates and incubated at 37°C and the diam-
eter of the inhibition zone around each disc was measured
after 24 h for antibacterial activity and after 74 h for antifun-
gal activity. Growth inhibition was calculated according to
−1
1
260 cm is attributed to the C─N─C stretching vibration
[27]
of the N(CH ) moiety.
appearing at 1610 cm for the azomethine group of free
The stretching vibration band
3
2
−1
−1
ligand is shifted to lower frequency (1571 cm in Cu(II);
−1
−1
−1
1
604 cm in Ni(II); 1598 cm in Co(II); 1597 cm in Zn
[
26]
the literature.
(II)) in the spectra of metal complexes, indicating that the
azomethine nitrogen is coordinated to the central metal ion
in all the complexes. The spectra are shown in Fig. S1. These
observed results clearly indicate that the coordination of the
Schiff base ligand to the metal centre has occurred as pro-
posed in the presented structure. Generally, for benzene and
its derivatives, the aromatic C─H in‐plane bending modes
3
| RESULTS AND DISCUSSION
The synthesized Schiff base ligand and the metal complexes
were found to be air‐stable at room temperature. The Schiff
base ligand was soluble in methanol. The Schiff base metal
complexes were insoluble in water, alcohol and chloroform
but soluble in DMSO. The molar conductivities (10−3 M)
of their solutions at room temperature were measured. The
lower conductance values of all the complexes in DMSO
showed that the chloride ions were present inside of the
coordination sphere which was confirmed by silver nitrate
test. Moreover, the lower molar conductance of these com-
plexes supported the non‐electrolytic nature of the metal
complexes. The results of elemental analysis of the metal
complexes were in good agreement with the calculated
−
1
are observed in the region 1100–1300 cm . For Cu(II), Ni
(II), Co(II) and Zn(II) complexes, these FT‐IR bands are
−1
observed at 1122, 1165, 1232 and 1240 cm , respectively.
The bands arising from ring C─H out‐of‐plane bending
vibrations are usually observed in the region 650–1000 cm
−
1
for complexes. The bands observed at 939, 812, 727 and
671 cm− are assigned to ring C─H out‐of‐plane bending
vibrations for the Cu(II), Ni(II), Co(II) and Zn(II) complexes,
respectively. Moreover, the formation of complexes is also
revealed by the presence of medium intensity (M─N) bands
at ca 420–450 cm which are not observed for the free
ligand.
1
−
1
[
28]
values of molecular formula [MLCl ], where M = metal
The M─Cl stretching bands appearing in the
2
−1
(II) and L = Schiff base ligand. The synthetic route to the
region below 400 cm further confirm the complex forma-
tion.
[
29]
Schiff base ligand and its metal complexes is shown in
Scheme 1.
In conclusion, these data suggest the N,N‐bidentate
behaviour of the ligand.

S. PACKIANATHAN ET AL.
5
+
3.2 | Electronic spectra of metal(II) chelates
corresponding to [C H N ] ion. Also, the spectrum
21 28 4
exhibited fragments at m/z 120, 147, 161 and 175
Electronic spectra of the Schiff base ligand and its metal
complexes were recorded in DMSO and are shown in
Fig. S2. The electronic absorption spectrum of the Schiff base
+
+
+
corresponding to [C H N] , [C H N ] , [C H N ]
8
10
9
11
2
10 13 2
+
and [C H N ] , respectively. The mass spectrum of the
11 15 2
−
1
Cu(II) complex showed peaks at m/z 468, 433, 399, 335 and
ligand displayed high‐energy bands at 363 nm (27 548 cm )
+
+
−
1
131 corresponding to [C21
H
N
28
+
CuCl
4
] , [C21H N CuCl] ,
2 28 4
and 258 nm (38 759 cm ), corresponding to π → π* transi-
tion of the aromatic ring and n → π* transition of C═N
groups, respectively. However, these bands were shifted to
+
[
C H N Cu] [C H N ] and [CuCl ], respectively. The
21
28
4
21 28
4
2
mass spectra of the ligand and Cu(II) complex are shown in
Figure 1. All the complexes underwent demetallation to form
−
1
−1
3
52 nm (28 409 cm ) and 246 nm (40 650 cm ) in the
+
the species [L] and provided fragment ion peak at m/z 335
spectra of the complexes. The Cu(II) complex displayed a
−
1
which corresponds to the molecular weight of the Schiff
base under investigation.
low‐intensity broad band at ca 472 nm (21 186 cm ) in
2
2
the visible region attributed to d–d ( B → A ) transition
1
g
1g
[
30]
and suggesting a square planar environment.
This geome-
try is further supported by its magnetic susceptibility value
1.94 BM). On the other hand, the Ni(II) complex showed a
lowest energy band appearing at 679 nm (14 727 cm ) due
3
.5 | Powder X‐ray diffraction
(
−1
We tried to isolate single crystals of the metal complexes
for accurate X‐ray crystal study but could not succeed in
developing single crystals; this might be because of the
powder or polycrystalline nature of complexes. Structural
information for most inorganic metal complexes is not
available because of the powder or polycrystalline nature
of these materials. Generally, it is difficult to grow good‐
quality single crystals of these inorganic complexes. In
such cases, powder X‐ray diffraction studies might be use-
ful. The X‐ray diffraction patterns of the metal complex are
shown in Fig. S3 which exhibit reflecting peaks of 2θ scat-
tering angles at 13.55°, 17.29°, 18.54°, 20.04°, 20.64°,
1
1
to d–d ( A1g → A ) transition as a result of its square planar
2g
[
31]
environment.
The electronic spectrum of the Co(II) com-
−
1
plex exhibits absorptions at 725 nm (13 793 cm ) and
−1
4
7
(
91 nm (12 642 cm ) which are assigned to T1g
4
4
4
F) → A (F) and A (F) → T (F) transitions, respec-
2g 2g 1g
tively, corresponding to a Co(II) square planar complex.
The geometry is further supported by its magnetic suscepti-
bility value (3.42 BM). In contrast, the Zn(II) complex does
not exhibit any d–d band because of its completely filled
1
0
d
electronic configuration.
2
2
1.14°, 23.44°, 24.35°, 24.66°, 25.80°, 26.42°, 26.82°,
7.37°, 28.30°, 28.85° and 29.65° allocated to the (hkl)
3
.3 | NMR spectra
1
crystal planes (−110), (020), (−104), (−202), (−122),
The H NMR spectra of the Schiff base ligand and the Zn(II)
complex were recorded in DMSO‐d6 solution using
tetramethysilane as an internal standard. The aromatic proton
signals appeared in the region 6.8–7.5 ppm. Schiff base is
supported by the presence of azomethine (HC═N) proton sig-
(
(
121), (−204), (104), (211), (114), (−222), (212), (−223),
−116), (131), (−224) and (−133), respectively, the charac-
teristics arrangement of Cu(II) atom (JCPDS no. 23–1904).
The standard JCPDS and observed 2θ data and d‐spacing
values are given in Table S2. The XRD pattern of the Ni
nal appearing at 8.7 ppm and a singlet peak at 3.1 ppm for
1
(II) complex displays the peaks of 2θ scattering angles at
(N─CH ) protons. The H NMR spectrum of the zinc com-
3
1
3
0.13°, 15.99°, 21.19°, 24.71°, 26.93°, 28.27°, 30.64°,
6.54°, 38.60° and 42.94° allocated to the (hkl) crystal
plex shows a singlet peak at 8.9 ppm (CH═N), multiplet
peaks at 6.8–7.5 ppm for the aromatic ring protons and a sin-
glet peak at 3.1 ppm for (N─CH ) protons. From these obser-
vations, it is inferred that only the azomethine group (CH═N)
is involved in metal coordination. The C NMR spectrum of
planes (110), (113), (−115), (−116), (402), (−133), (420),
−228), (−336) and (−246), respectively, the characteristic
well‐ordered arrangement of Ni(II) atom (JCPDS no. 52–
481). The observed and standard JCPDS data for 2θ and
3
(
1
3
2
the ligand showed signals of an aromatic carbon at 111.9–
d‐spacing values are given in Table S3. The Co(II) com-
plex exhibits peaks of 2θ scattering angles at 10.20°,
153.4 ppm, N─CH carbon at 41.3 ppm, N─CH carbon at
3
2
53.8 ppm and CH ─CH carbon at 32.2 ppm. Moreover,
2
2
1
6.81°, 20.82°, 23.68°, 24.85°, 26.99°, 39.52° and 41.18°
assigned to the (hkl) crystal planes (011), (112), (−311),
014), (−320), (023), (123), (306) and (117), respectively,
the characteristics arrangement of Co(II) atom (JCPDS no.
2–1986). The standard JCPDS and observed data for 2θ
the signal of the (HC═N) carbon at 160.8 ppm for the ligand
was shifted to 162.3 ppm upon coordination, indicating that
the (HC═N) group participates in complex formation.
(
7
3
.4 | Mass spectra
and d‐spacing values are given in Table S4. The Zn(II)
complex shows peaks of 2θ scattering angles at 14.71°,
18.78°, 19.89°, 20.67°, 23.23°, 25.78°, 26.87°, 28.90°,
33.77° and 38.29° which are assigned to the (hkl) crystal
planes (−101), (102), (112), (−111), (013), (200), (−201),
(202), (−2–21), (214), (225) and (−3–23), respectively,
Mass spectra provide crucial evidence for elucidating the
structure of compounds. The ESI mass spectra of the
ligand and its copper complex were recorded to evaluate
the stoichiometric composition. The spectrum of the Schiff
base showed
a
molecular ion peak at m/z 335

6
S. PACKIANATHAN ET AL.
FIGURE 1 ESI‐MS spectra of (a) Schiff base ligand and (b) Cu(II) complex
2
2
the characteristic well‐ordered arrangement of Zn(II) atom
copper site has a dx − y ground state attributed to square
[
32]
(JCPDS no. 89–1341). The standard JCPDS and observed
planar or octahedral stereochemistry.
A value of g > 2.3
||
data for 2θ and d‐spacing values are given in Table S5.
is characteristic of an ionic environment and g < 2.3 indi-
||
cates a covalent environment in metal–ligand bonding. The
observed g values of complexes are less than 2.3 suggesting
||
[
33]
3.6 | EPR spectra
that the environment is covalent.
In axial symmetry, the g‐values are related by the expres-
sion
The EPR spectrum of the copper complex was recorded in
the solid state at room temperature and is shown in Fig. S4
The spectrum exhibits axially symmetric g‐tensor parameters
with g (2.1552) > g (2.0230) > 2.003 indicating that the
À
Á
G ¼ g −2:0027 =ðg −2:0027Þ ¼ 4
∥
⊥
||
⊥

S. PACKIANATHAN ET AL.
7
[34]
According to Hathaway and Billing,
for a value of
to DNA through intercalation binding, usually the obtained
G > 4, the exchange interaction between Cu(II) centres in
the solid state is negligible, whereas if its value is <4, a con-
siderable exchange interaction is indicated in the solid com-
plex. The calculated G value for the copper complex is >4
suggesting that a copper–copper exchange interaction is neg-
results
indicate
hypochromism
and
red
shift
(bathochromism), due to the strong stalking interaction
among the aromatic chromophore of the complex and the
base pairs of DNA. The absorption spectra of the Cu(II) com-
plex in the absence and presence of CT DNA are shown in
Figure 2. The absorption spectra of copper, nickel, cobalt
and zinc complexes show intense absorption bands at
352.2, 353.3, 351.7 and 354.1 nm, respectively, in 5 mM
Tris–HCl/50 mM NaCl (pH = 7.2) buffer solution. Increasing
the concentration of CT DNA resulted in a minor
bathochromic shift in the range ca 2.8 to 2.2 nm and signifi-
cant hypochromicity lying in the range ca 11 to 7% for all the
complexes indicating appreciable intercalation binding of the
2
2
2
ligible. The bonding parameters (α , β and γ ) of the Cu(II)
complex have been calculated and are summarized in Table
S6. These bonding parameters may be regarded as a measure
of the covalency of the in‐plane σ‐bonds, in‐plane π‐bonds
2
and out‐of‐plane π‐bonds. Parameter α can be calculated
using the equation
À
Á
À
Á
2
α ¼ A =P þ g −2:0023 þ 3=7ðg −2:0023Þ þ 0:04
∥
∥
⊥
[
36]
complexes to CT DNA.
The equilibrium binding constant values are 4.3 × 10 ,
4
2
A value of α = 0.5 indicates pure covalent character
4
4
4
−1
3
.9 × 10 , 4.7 × 10 and 3.7 × 10 M for copper(II),
2
whereas α = 1.0 denotes pure ionic character. In the present
nickel(II), cobalt(II) and zinc(II) complexes. In order to com-
pare the binding strength of the complexes with CT DNA, the
intrinsic binding constants (K ) are obtained by monitoring
the changes in the absorbance for the complexes with increas-
ing concentration of DNA. K is obtained from the ratio of
2
case, the value of α (0.5966) of the [CuLCl ] complex indi-
2
cates that the complex has some covalent character. The out‐
b
2
2
of‐plane π‐bonding (γ ) and in‐plane π‐bonding (β ) parame-
ters have been calculated from the following expressions:
b
À
Á
À
Á
slope to intercept of a plot of [DNA]/(εa − ε ) versus
2
2
f
β ¼ g −2:0023 E= −8λα
∥
[
DNA]. The K values are given in Table 1.
b
2
2
γ ¼ ðg −2:0023ÞE=ð−2λα Þ
⊥
3
.7.2 | Viscosity measurements
2
2
The observed β (0.8320) and γ (0.4932) values for
CuLCl ] indicate that there is interaction in the out‐of‐plane
To further elucidate the interaction between the metal com-
plexes and DNA, viscosity measurements were studied. A
classic intercalative mode causes a considerable increase in
viscosity of DNA solution due to the increase in overall
DNA length. If the complexes bind completely in the DNA
grooves by partial and/or non‐classical intercalation under
similar conditions, then this typically causes less pronounced
(positive or negative) or no change in DNA solution viscos-
ity. The effect of increasing the amount of metal complexes
on the virtual viscosity of DNA is shown in Fig. S5 A gradual
increase in virtual viscosity was observed on accumulation of
the metal complexes to DNA solution suggesting essentially
[
2
π‐bonding whereas the in‐plane π‐bonding is completely
ionic. This fact is confirmed by orbital reduction factors
which are estimated using the following relations:
ÂÀ
Á
Ã
2
K ¼ g −2:0023 ΔE =8λ
K ¼ ½ðg −2:0023ÞΔEꢀ=8λ
∥
∥
0
2
⊥
⊥
0
where λ is the spin–orbit coupling constant for the Cu(II) ion
0
−
1
(
−828 cm ) and K and K are the parallel and perpendicu-
|
|
⊥
lar components of the orbital reduction factor (K). Significant
information about the nature of bonding in the Cu(II) com-
plex can be derived from the relative magnitudes of K and
K . In the case of pure σ‐bonding, K ≈ K ; whereas
K < K implies considerable in‐plane π‐bonding; while for
[37,38]
an intercalation mode of binding with the complexes,
||
i.e. the observed increase in the virtual viscosity of DNA
could be the result of an increase in the duplex length on
intercalation of the complexes. This observation may be elu-
cidated by the insertion of the compounds in between the
DNA base pairs, leading to an increase in the separation of
base pairs at intercalation binding sites and, for that reason,
⊥
||
⊥
|
|
⊥
out‐of‐plane π‐bonding, K > K . For the present case, the
||
⊥
observed order is K (0.4890) > K (0.2648) for [CuLCl ]
|
|
⊥
2
implying a greater contribution from out‐of‐plane π‐bonding
than from in‐plane π‐bonding in metal–ligand π‐bonding.
The calculated f‐factor (g /A ) is considered as an empirical
index of square planar distortion and is found to be 151,
which is characteristic for slight to moderate distortion.
[39]
an increase in overall DNA length. The observed viscosity
results are in accordance with absorption titration results.
||
||
[
35]
3
.7.3 | Fluorescence
In order to further investigate the interaction mode of the
Schiff base metal complexes with DNA, a competitive bind-
ing experiment using EB as a probe was carried out. EB is
a conjugate planar molecule with very weak fluorescence
intensity due to fluorescence quenching of the free EB by
3
.7 | Binding studies
3
.7.1 | Absorption titration
Absorption titration can be used to investigate the interaction
of metal complexes with DNA. In general, if a complex binds

8
S. PACKIANATHAN ET AL.
FIGURE 2 Absorption spectra of (a) [CuLCl
2
], (b) [NiLCl
2
], (c) [CoLCl
2
2
] and (d) [ZnLCl ] complexes in buffer (pH = 7.2) at 25°C in presence of increasing
amounts of DNA. Arrow indicates the changes in absorbance with increasing DNA concentration
TABLE 1 Electronic absorption spectral properties of Cu(II), Ni(II), Co(II)
and Zn(II) complexes with DNA
was incomplete quenching of the EB‐induced emission inten-
sity, the intercalative binding mode was ruled out. The extent
of quenching of the emission intensity gives a measure of the
binding propensity of the interacting molecule with CT DNA.
λ
max (nm)
a
−1 b
Compound
Δλ (nm)
H (%)
K
b
(M
)
Free
Bound
354.9
355.7
354.5
356.3
4
[
[
[
[
CuLCl
2
]
352.2
353.3
351.7
354.1
2.7
2.4
2.8
2.2
8.13
8.06
4.3 × 10
3.9 × 10
4.7 × 10
3.7 × 10
The Stern–Volmer quenching constant values, K , obtained
SV
4
4
4
NiLCl
2
]
as the slope of I /I versus r ([complex]/[DNA]) have been
0
CoLCl
2
]
10.84
7.89
evaluated for the Cu(II) and Co(II) complexes and found to
be 2.11 and 2.32, respectively.
2
ZnLCl ]
a
H = [(Afree − Abound)/Afree] × 100%.
b
Intrinsic DNA binding constant determined from UV–visible absorption spectral
3
.7.4 | Cyclic voltammetry
titration.
Cyclic voltammetric measurements of the Schiff base metal
complexes were carried out. The cyclic voltammograms of
the metal complexes in the absence and presence of varying
amounts of DNA are shown in Figure 4. The incremental
addition of CT DNA to the complexes causes a shift in the
potential peak in cyclic voltammograms. This result shows
that a complex stabilizes the duplex (GC pairs) by intercalat-
ing. Electrochemical parameters for the interaction of DNA
with [CuLCl ], [NiLCl ], [CoLCl ] and [ZnLCl ] metal(II)
solvent molecules, but it is greatly enhanced when EB is
intercalated into the adjacent base pairs of double‐stranded
DNA. The enhanced fluorescence can be quenched upon
the addition of a second molecule which could replace the
bound EB or break the secondary structure of the DNA. On
addition of metal complexes to CT DNA pretreated with
EB ([DNA]/[EB] = 1) a significant reduction in the emission
intensity (Figure 3) was observed, indicating the replacement
of the EB fluorophore by the complexes, which results in a
decrease of the binding constant of EB to DNA. As there
2
2
2
2
complexes are summarized in Table 2. The Ip /Ip ratios of
c
a
these four redox couples of the complexes are 0.7132,
0.5682, 0.6143 and 0.6415, respectively, which indicate that

S. PACKIANATHAN ET AL.
9
2 2
FIGURE 3 Emission spectra of [CuLCl ] and [CoLCl ] complexes in buffer (pH = 7.2) at 25°C in presence of increasing amounts of DNA
the reaction of the complexes on the glassy carbon electrode
surface is a quasi‐reversible redox process. The ratio of Ipa/
peak potentials in the presence of incremental addition of
CT DNA. Most of the synthesized complexes show both
anodic and cathodic peak potential shifts which are either
positive or negative (Table 2). This indicates the intercalating
mode of DNA binding with the Schiff base complexes.
Ip is approximately unity. This indicates the quasi‐reversible
c
redox process of the metal complexes. During the incremen-
tal addition of CT DNA to the complexes the redox couples
caused a negative shift in E1/2 and a decrease in ΔEp. Addi-
tion of CT DNA to the complexes causes a positive shift in
the potential and a decrease in the current intensity. From
these data, it is understood that all the synthesized complexes
3
.8 | DNA cleavage activity
The cleavage reaction was screened by gel electrophoresis.
The electrophoresis obviously indicated that the Schiff base
L and its metal(II) complexes have interacted with DNA as
there was a difference in the bands of lanes 1–5 compared
to the control DNA (Figure 6). The Schiff base metal com-
plexes are able to convert supercoiled DNA into open circular
DNA. In general, oxidative mechanisms account for DNA
cleavage by hydroxyl radicals via abstraction of a hydrogen
from sugar units and predict the release of specific residues
arising from transformed sugars, depending on the position
[40]
interact with DNA in an intercalating manner.
In addition, in differential pulse voltammograms of
[
MLCl ] in the absence and presence of varying amounts of
2
DNA with significant decrease of current intensity (Figure 5),
the shift in potential is related to the ratio of binding constants
by the following equation:
À
Á
E −E ¼ 0:0591× log K =K
b
f
½redꢀ
½oxꢀ
[
41]
where E and E are peak potentials of the complex in bound
from which the hydrogen is removed.
The reaction is
b
f
and free forms, respectively. The present Schiff base com-
plexes show one‐electron transfer during the redox process
and the Ip /Ip value is less than unity which indicates the
reaction of the complexes on the glassy carbon electrode sur-
face is quasi‐reversible. Other complexes (Co(II), Ni(II) and
Zn(II)) show considerable shift in both cathodic and anodic
modulated by a bound hydroxyl radical or a peroxo species
generated from H O . In this study, the pUC19 DNA gel
2
2
electrophoresis experiment was conducted at 35°C using the
synthesized complexes in the presence of H O as oxidant.
a
c
2
2
From Figure 6, it is observed that the control DNA (lane 1)
does not show any significant cleavage of pUC19 DNA even

1
0
S. PACKIANATHAN ET AL.
FIGURE 4 Cyclic voltammograms of (a) [CuLCl
2
], (b) [NiLCl
2
], (c) [CoLCl
2
] and (d) [ZnLCl
2
] complexes in buffer (pH = 7.2) at 25°C in presence of
increasing amounts of DNA
TABLE 2 Electrochemical parameters for interaction of DNA with Cu(II),
Ni(II), Co(II) and Zn(II) complexes
that the compounds inhibit the growth of pathogenic organ-
isms by cleaving the genome.
a
a
b
E1/2 (V)
ΔEp (V)
a c
Ip /Ip
Compound
Free
Bound
0.134
0.021
0.141
0.009
Free
Bound
−1.615
−1.42
3
.9 | Molecular docking with DNA
[
[
[
[
CuLCl
2
]
0.112
0.007
0.125
0.003
−1.646
−1.448
−1.681
−1.719
0.7132
0.5682
0.6143
0.6415
NiLCl
2
]
The docking of the Schiff base ligand complexes with DNA
was performed to rationalize the results of DNA binding
study. The best docked poses are shown in Figure 7. It is
obvious that the metal complexes get attached to DNA
through intercalation binding mode between the nucleotide
base pairs of DNA. Energetically favourable docked poses
were obtained from the rigid molecular docking experiments
agreeing between the optimized energy‐minimized structures
(Figure 7) for the ligand and Cu(II), Ni(II), Co(II) and Zn(II)
CoLCl
2
]
−1.676
−1.769
2
ZnLCl ]
a
Data from cyclic voltammetric measurements. E1/2 is calculated as the average of
anodic (Ep ) and cathodic (Ep ) peak potentials: E1/2 = (Ep + Ep )/2;
− Ep
a
c
a
c
ΔEp = Ep
a
c
.
b
Error limit: ±5%.
for longer exposure time. Co(II) and Cu(II) complexes (lanes
and 5) cleave DNA as compared to control DNA while the
other complexes do moderately cleave in the presence of
4
complexes with DNA duplex of sequence
d
(CGCGAATTCGCG)2 dodecamer (PDB ID: 1BNA). On
analysing the docked structures, it is evident that the metal
complexes fit well into the A‐T rich region of target DNA.
The Schiff base and its metal complexes are stabilized in
the A‐T rich region through various interactions, such as
[
42]
H O . The results indicate the presence of radical cleavage
2
2
and the cleavage efficiency of the complexes is comparable to
the control, due to their efficient DNA‐binding ability. As the
compounds were observed to cleave DNA, it is concluded

S. PACKIANATHAN ET AL.
11
FIGURE 5 Differential pulse voltammograms of (a) [CuLCl
2
], (b) [NiLCl
2
], (c) [CoLCl
2
] and (d) [ZnLCl
2
] complexes in buffer (pH = 7.2) at 25°C in the
presence of increasing amounts of DNA
[
43]
van der Waals and hydrophobic interactions.
The Schiff
base ligand and its Cu(II), Ni(II), Co(II) and Zn(II) metal
complexes have docking scores of −212.34, −225.57,
−224.18, −225.20 and −223.95, respectively. A compound
with a higher negative docking score is deemed as more
potent. In the present study, Cu(II) and Co(II) complexes
have higher docking scores and hence they have more activ-
ity. Minimum activity is found for the Schiff base ligand as
it has a low docking score of −212.34.
3
.10 | Antimicrobial activity
Antibacterial activity of the Schiff base ligand and its metal
complexes was determined using the paper disc method.
The Schiff base ligand and its complexes were screened
against four bacterial strains, K. pneumoniae, B. subtilis, E.
coli and S. typhi, and the fungi A. flavus, A. niger and C.
albicans. The results presented in Table 3 reveal that Schiff
base ligand and its complexes have some activity, but they
are not as active as the standard drugs (ampicillin for bacteria
FIGURE 6 Gel electrophoretic separation of plasmid pUC19 DNA treated
with [MLCl ] complexes. Lane 1: DNA + ligand + H ; Lane 2: DNA +
] + H ; Lane 3: DNA + [NiLCl ] + H ; Lane 4: DNA +
] + H ; Lane 5: DNA + [CuLCl ] + H
2
2 2
O
[
[
ZnLCl
CoLCl
2
2
O
2
2
2 2
O
O
2 2
2
2
O
2
2

1
2
S. PACKIANATHAN ET AL.
2 2
FIGURE 7 Interaction of the complexes [NiLCl ] and [ZnLCl ] with d(CGCGAATTCGCG) strands of DNA
TABLE 3 In vitro antimicrobial activity of Schiff base and its metal complexes (zone of inhibition in mm)
Bacteria
Fungi
Compound
E. coli
8
B. subtilis
K. pneumoniae
S. typhi
11
A. flavus
C. albicans
A. niger
18
L
10
20
22
17
21
29
—
13
23
16
21
15
24
—
19
27
20
24
19
—
35
15
19
24
20
22
—
30
[
[
[
[
CuLCl
2
]
21
21
26
NiLCl
2
]
19
15
21
CoLCl
2
]
20
23
27
ZnLCl
2
]
17
17
22
a
Ampicillin
Ciprofloxacin
26
22
—
b
—
35
a
Ampicillin was used as the standard for bacteria.
b
Ciprofloxacin is used as the standard for fungi.

S. PACKIANATHAN ET AL.
13
and ciprofloxacin for fungi). However, the results reveal that
the metal complexes have a higher inhibitory activity than the
Schiff base ligand against both Gram‐positive and Gram‐neg-
ative bacteria.
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[
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The metal complexes show better antimicrobial activity
than the ligand. According to the Overtone concept of cell
permeability, the lipid membrane surrounding a cell favours
the passage of only lipid‐soluble materials, and therefore
liposolubility is an important factor which controls antimicro-
bial activity. On chelation, the polarity of the metal ion is
reduced to a greater extent due the overlapping of the ligand
orbital and partial sharing of the positive charge of the metal
ion with donor groups. The resulting increased lipophilicity
enhances the penetration of the complexes into the lipid
membranes and blocks the metal binding sites in the enzymes
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[
[
[
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In this study, a biologically significant Schiff base ligand and its
Cu(II), Ni(II), Co(II) and Zn(II) metal complexes have been
synthesized and characterized. The physicochemical and spec-
tral data reveal that all the complexes are mononuclear and
adopt square planar geometry around the metal ion. The Schiff
base complexes bind to CT DNA and such binding ability has
been explored using diverse techniques. The data obtained
prove that the complexes act as efficient metallointercalators.
The agarose gel electrophoresis studies show that the com-
plexes can promote the oxidative cleavage of plasmid DNA.
However, these observations and a more extensive study would
be necessary in order to assert that the complexes act as cleav-
age agents. The docked structures reveal that the complexes can
fit well with intercalative binding of DNAwith a binding site of
three base pairs preferably involving the A‐T residues. The
biological data indicate that the complexes have higher antimi-
crobial activity than the free Schiff base ligand. The coopera-
tive biological activities of the complexes may be helpful for
the design of metal‐based drugs.
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